Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an extremely low 5-year survival rate even for those who are diagnosed early. Novel research suggests that this may be the result of metastatic dissemination preceding or concurrent to the development of the primary tumor. Epithelial- mesenchymal transition (EMT) is one of the key pathways in pancreatic cancer invasion and metastasis and is linked to a tumor stem cell phenotype. The COARE Biotechnology R&D team believes that targeting this process will ultimately allow us to significantly increase patient survival. COARE's primary expertise is in targeting cancer through the doublecortin-like kinase 1 (DCLK1) tumor stem cell marker. During COARE's Phase I SBIR study of a mouse monoclonal antibody (mAb) raised against DCLK1 (CBT-1111) that showed promising results in vitro and in vivo, COARE Biotechnology engineered a newer generation of mAb designed to take advantage of DCLK1's cell surface antigen expressed on pancreatic cancer tumors, circulating tumor cells, and metastases, which led to a powerful anti-tumorigenic effect in PDAC tumor xenografts. For this Phase II project, we propose to further develop this mAb, termed raphtumomab, in preparation for commercialization and human clinical trials. We will pursue this objective with the following three specific aims: Aim 1: COARE, in collaboration with Panorama Research Institute, will humanize raphtumomab to create raphtuzumab and will confirm retained binding affinity for DCLK1 by BIAcore and other techniques. Aim2: COARE, in collaboration with the University of Oklahoma Health Sciences Center, will assess raphtuzumab to determine its pharmacokinetic/dynamic (PK/PD) properties, mechanism of action (MOA), and its continued preclinical efficacy in patient-derived orthotopic models of PDAC. Aim 3: COARE, in collaboration with WIL Research, will perform IND-enabling toxicity and immunogenicity studies of raphtuzumab in Sprague-Dawley rats (SDR) and non-human primates (NHPs). Milestones: Raphtuzumab will demonstrate retained DCLK1 affinity (1 nM); a DCLK1 MOA (>70% reduction in EMT and DCLK1 expression); continued preclinical efficacy including a >3-fold reduction in patient-derived orthotopic model tumorigenesis; suitable PK/PD, toxicity, and immunogenicity in SDR and NHPs. Desired Outcome: Phase II SBIR success provide the key results and data needed to engage private-sector investors/partners in carrying out the next steps toward the regulatory approval required to begin clinical trials in PDAC patients. Success with the clinical trials will lead to ultimate commercialization. When raphtuzumab reaches the market, COARE Biotechnology envisions that it will be the first treatment for PDAC that can significantly increase patient overall survival.